ABSTRACT Radiation therapy (RT) is a very effective treatment modality for improving local control and overall survival for many cancer types. However, glioblastoma multiforme (GBM) displays remarkable radioresistance. Although, post-surgical RT (total dose of 60Gy in 2Gy fractions) is the only treatment modality that increases overall survival for GBM patients, GBM universally recurs and is fatal. Resistance to RT is therefore a major contributor to treatment failure. Overcoming radiation resistance of these tumors is one of the major remaining frontiers in Radiation Oncology that, if resolved, could dramatically improve outcomes in this disease. Amongst the many contributing factors that have been proposed, GBM metabolism and its role in generating resistance to oxidative stress, such as during RT is a promising therapeutic angle that we will exploit in this proposal. Specifically, we have evidence that irradiated GBM cells reprogram their metabolism towards antioxidant pathways, by funneling glucose through the NADPH- generating pentose phosphate pathway (PPP). Such metabolic reprogramming during RT is mediated in part by the glycolytic enzyme PKM2 and in part by the transcription factor NRF2. Oxidative stress-dependent inactivation of PKM2 or activation of NRF2, both result in rerouting of glycolytic intermediates into the PPP. In addition, we have evidence that PKM2 is a NRF2 target. Therefore, we hypothesize that PKM2 and NRF2 cooperate in driving an antioxidant metabolic response in irradiated GBM cells that promotes resistance to RT. Of importance is the fact that PKM2 is overexpressed in GBM tumors, while normal brain tissue only expresses PKM1. Also, small molecule activators of PKM2 are available that exacerbate oxidative stress and have anti-tumor activity, although they have not been tested in GBM or with RT. These activators cross the blood brain barrier making them suitable for combining with RT to sensitize GBM tumors. Therefore, it is also proposed that interfering with the NRF2-PKM2-metabolism axis would limit the antioxidant, pro-survival metabolic reprogramming induced by radiation and improve the effect of RT in human and mouse models of GBM.